Existing studies provide evidence that the host factors play important roles in the control of human immunodeficiency virus type 1 (HIV-1) replication during primary HIV-1 infection and in the subsequent course of HIV-1 related disease and the development of the acquired immunodeficiency syndrome (AIDS). Available data suggest that viral replicative fitness is an important determinant of HIV-1 virulence and that modulation of HIV-1 replicative fitness with antiretroviral therapy attenuates HIV-1 pathogensis. However, relatively little is known about how the virulence of the virus that is transmitted during primary HIV-1 infection contributes to disease pathogenesis, and the molecular basis for differences in transmitted virus virulence are largely unknown. The studies proposed in Project 5 of this program project application will evaluate the central hypothesis that differences in the replicative fitness of HIV-1 that is transmitted during primary infection is an important factor in natural history of HIV-1 infection. The specific aims of this project are: 1) Determine the relationship between fitness of recently transmitted virus and steady state HIV-1 viremia after acute HIV-1 infection. If differences in transmitted virus fitness are found, the molecular basis for fitness differences will be explored. 2) Determine if transmitted HIV-1 replication rates are different for subjects who control, or do not control HIV-1 replication after interruption of antiretroviral therapy initiated during acute HIV-1 infection. 3) Compare transmitted virus replicative fitness in HIV-1 subtype B and C infection. If differences in subtype fitness are found, the contributions of divergent reverse transcriptase, protease and envelope genes will be determined. It is expected that the results of the proposed studies will provide new insight into the mechanisms of HIV-1 pathogenesis and that this information will be useful for the development of new strategies for the prevention and treatment of HIV-1 infection.